drugs acting on calcium balance, parathyroid hormone, calcitonin, vitamin D, bisphosphonates, treatment of osteoporosis

1. DRUGS ACTING ON CALCIUM
BALANCE

2. • Ca salts in bone provide structural integrity of the skeleton.
• Ca is the most abundant mineral in the body.
• Ca ions in extracellular and cellular fluids is essential to normal
function of a host of biochemical processes
• Neuromuscular excitability and signal transduction
• Blood coagulation
• Hormonal secretion & Enzymatic regulation
• Ca controls the impulse generation in heart

3. • About 1000 mg of Ca is ingested per day.
• About 200 mg of this is absorbed into the body.
• Absorption occurs in the small intestine, and requires vitamin D
• Milk and dairy products - Egg yolk , Fish, beans
• Cow’s milk 100mg/100ml
• Human milk 30mg/100ml

4. • About 1000 mg of Ca is ingested per day.
• About 200 mg of this is absorbed into the body.
• Absorption occurs in the small intestine, and requires vitamin D
• Milk and dairy products - Egg yolk , Fish, beans
• Cow’s milk 100mg/100ml
• Human milk 30mg/100ml

5. A) Factors favoring calcium absorption
• An acidic pH
• Presence of sugar acids, organic acids and citric acid
• High protein diet- Lysine and Arginine cause absorption
• Presence of vitamin D
• Ca : P ratio
• State of health and intact mucosa
• PTH (Parathormone)

6. B) Factors inhibiting absorption of calcium
• Alkaline pH
• High fat diet
• Presence of Phytates and oxalates
• Dietary fiber in excess inhibits absorption
• Excess phosphates, magnesium and iron
• Glucocorticoids
• Calcitonin
• Advancing age and intestinal inflammatory disorders

7. • Vit D and PTH increase, while calcitonin decreases tubular
reabsorption of Ca2
• About 300 mg of endogenous calcium is excreted daily: half in urine
and half in faeces.
• Calcium absorption is greater in presence of calcium deficiency and
low dietary calcium.
• Thiazide diuretics impede calcium excretion by facilitating tubular
reabsorption.

8. • Plasma calcium level It is precisely regulated by 3 hormones
parathormone (PTH),
calcitonin and
calcitriol (active form of vit D).
• Normal plasma calcium is 9–11 mg/dl.
• 40% is bound to plasma protein albumin

10. Preparations
• Calcium carbonate (40% Ca)
• Calcium citrate (as tetrahydrate, 21% Ca2+)
• Calcium gluconate (9% Ca)
• Calcium lactate
• Calcium dibasic phosphate (23% Ca)
• Calcium chloride (27% Ca)
Side effects:
• constipation, bloating and excess gas

11. USES:
1. Tetany
• For immediate treatment of severe cases 10–20 ml of Cal. gluconate
(elemental calcium 90–180 mg) is injected i.v. over 10 min, followed
by slow i.v. infusion.
• A total of 0.45- 0.9 g calcium (50 to 100 ml of cal. Gluconate solution)
over 6 hours is needed for completely reversing the muscle spasms.
• Supportive treatment with i.v. fluids and oxygen inhalation
• Long-term oral treatment to provide 1–1.5 g of calcium daily is
instituted along with vit. D.

12. 2. As dietary supplement
• In growing children, pregnant, lactating and menopausal women.
• Calcium supplement can reduce bone loss in predisposed women as
well as men
3. Cal. gluconate i.v. has been used in dermatoses, paresthesias,
weakness and other vague complaints.
4. As antacid

13. 5. Osteoporosis
• In the prevention and treatment of osteoporosis with
alendronate/HRT/ raloxifene, it is important to ensure that calcium
deficiency does not occur.
• Calcium + vit D3 have adjuvant role to these drugs in prevention and
treatment of osteoporosis.

14. PARATHYROID HORMONE
• PTH is a single chain 84 amino acid polypeptide
• Secretion of PTH is regulated by plasma Ca2+ concentration through a
calcium-sensing receptor (CaSR), that is a G-protein coupled receptor
on the surface of parathyroid cells.
• Fall in plasma Ca2+ induces PTH release and rise inhibits secretion
• The active form of vit. D calcitriol inhibits expression of PTH gene in
parathyroid cells reducing PTH production.
• PTH is rapidly degraded in liver and kidney;
• Plasma t½ is 2-5 mins

15. • Actions
PTH increases plasma calcium levels by:
1. Bone
• PTH promptly increases resorption of calcium from bone.
• Bone deposition is also promoted by PTH
• Increased bone formation occurs when PTH is given intermittently
and in low doses.

16. 2. Kidney
• PTH increases calcium reabsorption in the distal tubule
• promotes phosphate excretion
3. Intestines
• PTH has no direct effect on calcium absorption but increases it
indirectly by enhancing the formation of calcitriol
4. PTH decreases calcium levels in milk, saliva and ocular lens. This may
be responsible for development of cataract in hypoparathyroidism

17. MECHANISM OF ACTION

18. Hypoparathyroidism:
• Manifestations are:
• Low plasma calcium levels, tetany, convulsions, laryngospasm,
paresthesias, cataract and psychiatric changes.
Pseudohypoparathyroidism occurs due to reduced sensitivity of target
cells to PTH

19. Hyperparathyroidism
• It is mostly due to parathyroid tumour.
• It produces—Hypercalcaemia, decalcification of bone—deformities
and fractures (osteitis fibrosa generalisata), metastatic calcification,
renal stones, muscle weakness, constipation and anorexia.
• Treatment is surgical removal of the parathyroid tumour.
• When this is not possible—low calcium, high phosphate diet with
plenty of fluids is advised.

20. Cinacalcet
• It activates the Ca2+ sensing receptor (CaSR) in the parathyroids and
blocks PTH secretion.
• It is indicated in secondary hyperparathyroidism due to renal disease
and in parathyroid tumour.

21. Use
• PTH is not used in hypoparathyroidism because plasma calcium can
be elevated and kept in the normal range more by vit D therapy
• PTH has to be given parenterally, while vit D can be given orally. Vit D
is cheap

22. TERIPARATIDE
• Recombinant preparation of human PTH has been recently
introduced for the treatment of severe osteoporosis.
• It duplicates all the actions of long (1–84) PTH.
• Injected s.c. 20 μg once daily, it acts only for 2–3 hours,
• Increase bone mineral density in osteoporotic women.
• The effect was faster and more marked than that produced by
estrogens and bisphosphonates (BPNs).
• Teriparatide is the only agent which stimulates bone formation
• Plasma t½ is 1 hr; given once daily

23. • Limitations - High cost and need for daily s.c. injections
• Its use may be justified in severely osteoporotic women, those who
have already suffered osteoporotic fractures or have multiple risk
factors for fracture.
• Treatment beyond 2 years is not recommended.
• Side effects - dizziness and leg cramps.
• Contraindications - Pagets disease and hypercalcaemia
• Diagnostic use: To differentiate pseudo from true hypoparathyroidism
• Teriparatide is given i.v.: if plasma calcium level fails to rise, then it is
pseudohypoparathyroidism

24. CALCITONIN
• Calcitonin is the hypocalcaemic hormone discovered by Copp in 1962.
• Secreted by parafollicular ‘C’ cells of thyroid gland
• Synthesis and secretion of calcitonin is regulated by plasma Ca2+
concentration itself: rise in plasma Ca2+ increases, while fall in plasma
Ca2+ decreases calcitonin release
• The plasma t½ of calcitonin is 10 min, but its action lasts for several
hours

25. Mechanism of action
• It inhibits bone resorption by direct action on osteoclasts
• Calcitonin inhibits proximal tubular reabsorption of calcium and
phosphate by direct action on the kidney.
Preparation and unitage:
• Synthetic salmon calcitonin is used clinically, because it is more
potent and longer acting due to slower metabolism. Human calcitonin
has also been produced.
• 1 IU = 4 μg of the standard preparation

26. Side effects:
• Nausea, flushing and tingling of fingers is frequent after calcitonin
injection.
• Bad taste, flu-like symptoms, allergic reactions and joint pain are the
other adverse effects.

27. USES
1. Hypercalcaemic states:
• Hyperparathyroidism, hypervitaminosis D, osteolytic bony metastasis
and hypercalcaemia of malignancy - 4–8 IU/kg i.m. 6–12 hourly only
for 2 days.
• It acts rapidly within 4 hours, the response peaks at 48 hours and
then refractoriness develops. It also relieves bone pain.
• For emergency treatment of hypercalcaemia 5–10 IU/kg may be
diluted in 500 ml saline and infused i.v. over 6 hours.
• Calcitonin is a relatively weak hypocalcaemic drug.
• Therefore, used only to supplement BPNs initially, because BPNs take
24–48 hours to act.

28. 2. Postmenopausal osteoporosis
• A nasal spray formulation delivering 200 IU per actuation is
employed.
• One spray in alternate nostril daily has been shown to increase bone
mineral density in menopausal women and to reduce vertebral,
fractures
• Though nausea and flushing are less with nasal spray, rhinitis,
epistaxis, nasal ulceration and headache are produced frequently

29. 3. Paget’s disease
• 100 IU i.m./s.c. daily or on alternate days produces improvement for
few months.
• Bisphosphonates are preferred
• Calcitonin may be used as adjuvant or 2nd line drug.
4. Diagnosis of medullary carcinoma of thyroid

30. VITAMIN D
• D1 : mixture of antirachitic substances found in food—only of historic
interest
• D2 : calciferol—present in irradiated food— yeasts, fungi, bread, milk.
• D3 : cholecalciferol — synthesized in the skin under the influence of
UV rays.

31. 7-DEHYDROCHOLESTEROL ERGOSTEROL
UV light
CHOLECALCIFEROL (Vit D3) CALCIFEROL (Vit D2)
liver
CALCIFEDIOL (25-OH-D3) 25-OH-D2
kidneys
CALCITRIOL (1,25 (OH)2D3) 1,25 (OH)2D2

32. Thus, vit D should be considered a hormone because:
• (a) It is synthesized in the body (skin); under ideal conditions it is not
required in the diet.
• (b) It is transported by blood, activated and then acts on specific
receptors in the target tissues.
• (c) Feedback regulation of vit D activation occurs by plasma Ca2+ level
and by the active form of vit D itself.

33. • Actions
1. Calcitriol enhances absorption of calcium and phosphate from
intestine
• It binds to a cytoplasmic vitamin D receptor (VDR) → translocate to
the nucleus → increase synthesis of specific mRNA → regulation of
protein
2. Calcitriol enhances resorption of calcium and phosphate from bone
by promoting recruitment and differentiation of osteoclast precursors
in the bone remodeling units

34. • Calcitriol induces RANKL in osteoblasts which may then activate the
osteoclasts.
• Osteoblastic cells express VDR and respond to calcitriol by laying
down osteoid, but it mainly appears to help bone mineralization
3. Calcitriol enhances tubular reabsorption of calcium and phosphate in
the kidney

35. Vit D deficiency:
• Plasma calcium and phosphate tend to fall due to inadequate
intestinal absorption.
• PTH is secreted → calcium is mobilized from bone in order to restore
plasma Ca2+.
• The bone fails to mineralize normally in the newly laid area, becomes
soft → rickets in children and osteomalacia in adults.
• However, in contrast to osteoporosis, the organic matrix (osteoid) is
normal in these conditions

36. Hypervitaminosis D:
• It may occur due to chronic ingestion of large doses (~50,000 IU/day)
or due to increased sensitivity of tissues to vit D.
• Manifestations are due to elevated plasma calcium and its ectopic
deposition.
• These are:
• hypercalcaemia, weakness, fatigue, vomiting, diarrhoea, sluggishness,
polyuria, albuminuria, ectopic Ca2+ deposition (in soft tissues, blood
vessels, parenchymal organs), renal stones or nephrocalcinosis,
hypertension, growth retardation in children. Even coma has been
reported.
• Treatment: consists of withholding the vitamin, low calcium diet,
plenty of fluids and corticosteroids.

37. Pharmacokinetics
• Vit D is well absorbed from the intestines in the presence of bile salts,
• Malabsorption and steatorrhoea interfere with its absorption.
• It is bound to a specific α globulin and is stored in the body, mostly in
adipose tissues, for many months.
• It is hydroxylated in the liver to active and inactive metabolites.
• The t½ of different forms varies from 1–18 days:
• 25-OHD3, having the longest t½ , constitutes the primary circulating form.
• Calcitriol is cleared rapidly.
• Metabolites of vit D are excreted mainly in bile

38. Unitage and preparations
• 1 μg of cholecalciferol = 40 IU of vit D.
• The daily requirement varies, depending on exposure to sunlight
• Dietary allowance of 400 IU/day will prevent deficiency symptoms.
However, higher amounts (upto 1000 IU/day) are also recommended.

39. • The forms in which vit D is supplied are—
1. Calciferol (Ergocalciferol, vit D2) As solution in oil, filled in gelatin
capsules 25,000 and 50,000 IU caps.
2. Cholecalciferol (vit D3) As granules for oral ingestion and oily
solution for i.m. Injection
3. Calcitriol 0.25–1 μg orally daily or on alternate days;
Hypercalcaemia is the main adverse effect; must be watched for and
therapy promptly stopped if plasma Ca2+ rises.

40. 4. Alfacalcidol- It is 1 α-OHD3—a prodrug
• It is effective in renal bone disease, vit D dependent rickets, vit D
resistant rickets, hypoparathyroidism, osteoporosis.
• Alfacalcidol is orally active and clinically equally effective on long term
basis to calcitriol.
• Its metabolic activation in liver does not pose a problem even in
severe liver disease.
• Dose: 1–2 μg/day, children < 20 kg 0.5 μg/day.
• Repeated serum calcium measurements are essential for regulation of
maintenance dose.
• Hypercalcaemia should be watched for and therapy promptly
interrupted for few days when it develops.

41. 5. Dihydrotachysterol :
• A synthetic analogue of vit D2
• Directly mobilizes calcium from bone after 25-hydroxylation in liver,
and does not require PTH dependent activation in the kidney.
• It is particularly useful in hypoparathyroidism and renal bone disease.
• Dose: 0.25–0.5 mg/day.

42. USE
1. Prophylaxis (400 IU/day) and treatment (3000–4000 IU/day) of
nutritional vit D deficiency This is given to prevent and treat rickets in
children and osteomalacia in adults.
• Alternatively 300,000–600,000 IU can be given orally or i.m. once in
2–6 months.
• Prophylactic treatment may be given in obstructive jaundice,
steatorrhoea and other conditions which predispose to vit D
deficiency.

43. 2. Metabolic rickets
a) Vit D resistant rickets:Administration of phosphate with high dose
of calcitriol or alfacalcidol is beneficial.
(b) Vit D dependent rickets: Administration of calcitriol or alfacalcidol
is effective in normal doses
(c) Renal rickets: Calcitriol/alfacalcidol or dihydrotachysterol are
needed in usual doses.

44. 3. Senile or postmenopausal osteoporosis
• Vit D3 + calcium have been to improve calcium balance in
osteoporotic females and elderly males
• Calcitriol therapy carries the risk of hypercalcaemia, calcium stones
and metastatic calcification which should be watched for

45. 4. Hypoparathyroidism
• Dihydrotachysterol or calcitriol/alfacalcidol are more effective than
vit, D2 or D3
• Conventional preparations of vit D3 may be given in high doses
(25000-100,000 IU/day).
5. Fanconi syndrome Vit D can raise the lowered phosphate levels
6. Calcipotriol (DAIVONEX 0.005% oint) is used locally in plaque type
psoriasis

46. BISPHOSPHONATES
First generation BPNs
• Etidronate
• Tiludronate
Second generation BPNs
• Pamidronate
• Alendronate
• Ibandronate
Third generation BPNs
• Risedronate
• Zoledronate

47. • They inhibit bone resorption
• Accelerated the apoptosis of osteoclasts reducing their number.
• Have metabolic effects in the mevalonate pathway for lipid synthesis
inhibit prenylation of certain GTP-binding proteins involved in
cytoskeletal organization, membrane ruffling and vesicle movement.
• Inactivation of osteoclasts, impaired vesicle fusion and enhanced
apoptosis.
• Also impart antitumor action on bony metastasis

48. • poorly absorbed
• Produce gastric irritation, esophagitis
• They are contraindicated in gastroesophageal reflux, peptic ulcer and
renal impairment

49. USES:
1. Osteoporosis
• They are the first choice drugs for osteoporosis.
• Since the t½ of alendronate in bone is ~ 10 years, treatment beyond 5
years is considered unnecessary.
• The second and third generation BPNs (e.g. alendronate, risedronate)
are effective in preventing and treating postmenopausal osteoporosis
in women as well as age related, idiopathic and steroid-induced
osteoporosis in both men and women

50. 2. Paget’s disease
• They arrest osteolytic lesions, reduce bone pain and improve
secondary symptoms
• Alendronate, risedronate, pamidronate and zoledronate are used
• They are more convenient, more effective and cheaper than
calcitonin.

51. 3. Hypercalcaemia of malignancy
• is a medical emergency with altered consciousness.
• Pamidronate (60–90 mg i.v. Over 2–4 hours) or zoledronate (4 mg i.v. over
15 min) are the most effective drugs, but take 24–48 hours to act.
• They may be supplemented by i.m. calcitonin 6–12 hourly for 2 days to
achieve rapid action.
• Vigorous i.v. hydration is instituted first.
• After volume repletion, furosemide is added to enhance Ca2+ excretion
and to prevent volume overload. This is followed by BPN infusion.

52. 4. Osteolytic bone metastasis
• Parenteral pamidronate/zoledronate arrests osteolytic lesions and
reduces bone pain.

53. Etidronate
• This is the first BPN to be used clinically
• Employed in hypercalcaemia and Paget’s disease.
• It also interferes with bone mineralization
• Continuous therapy produces osteomalacia.
• Replaced by zoledronate for hypercalcaemia and alendronate/risedronate
for Paget’s disease.
• Etidronate is administered both orally and i.v., but is not preferred now.
• Dose: 5–7.5 mg/kg/day

54. Pamidronate:
• A second generation potent BPN
• Administered only by i.v. infusion in a dose of 60–90 mg over 2–4
hours weekly or monthly depending on the condition.
• It is used in Paget’s disease, hypercalcaemia of malignancy and in
bony metastasis.
• Adverse effects are thrombophlebitis of injected vein, bone pain,
fever and leukopenia.
• A flu-like reaction may occur

55. Alendronate
• This potent orally effective second generation amino-BPN
• Used for prevention and treatment of osteoporosis both in women
and men, as well as for Paget’s disease.
• It is to be taken on empty stomach in the morning with a full glass of
water and patient is instructed not to lie down or take food for at
least 30 m
• Calcium, iron, antacids, mineral water, tea, coffee, fruit juice interfere
with alendronate absorption.
• NSAIDs accentuate gastric irritation caused by alendronate.
• Adverse effects are gastric erosion, retrosternal pain, flatulence,
headache, bodyache and initial fall in serum Ca2+ level.
• Dose: 5–10 mg OD; or 35–70 mg weekly

56. Risedronate :
• It is an oral 3rd generation BPN,
• More potent than alendronate, but equally efficacious.
• Oral bioavailability of 1% and other features are similar to
alendronate.
• It is indicated in the treatment of osteoporosis and Paget’s disease.
• Dose: 35 mg/week oral in the morning with a full glass of water.

57. Zoledronate
• This parenteral highly potent 3rd generation BPN
• Indicated for hypercalcaemia, bony metastasis, osteolytic lesions, and
Paget’sdisease.
• For hypercalcaemia, it is more effective, faster acting than
pamidronate and therefore the drug of choice now.
• Advantage is that it can be infused over 15 min (because of less
venous irritation), whereas pamidronate needs 2–4 hours.
• Flu-like symptoms due to cytokine release attend the i.v. infusion

58. • Complication: Nausea, vomiting, bodyache, dizziness, Renal toxicity,
Osteonecrosis of the jaw
• Zoledronate 4 mg infused i.v. once every 12 months has been used for
osteoporosis in postmenopausal women who do not tolerate oral
alendronate/risedronate.
• Dose: 4 mg diluted in 100 ml saline/glucose solution and infused i.v.
over 15 min; may be repeated after 7 days and then at 3–4 week
intervals

59. Other drugs for hypercalcaemia
1. Gallium nitrate:
• It is a potent inhibitor of bone resorption;
• Acts by depressing ATP-dependent proton pump at the ruffled
membrane of osteoclasts.
• Indicated in resistant cases of hypercalcaemia,
• it is given by continuous i.v. infusion daily for 5 days.
• It is nephrotoxic and only a reserve drug.

60. 2. Glucocorticoids:
• High doses of prednisolone (and others)
• Enhance calcium excretion, decrease calcium absorption and
• Have adjuvant role in hypercalcaemia due to lymphoma, myeloma,
leukaemia, carcinoma breast, etc.

61. Drugs for osteoporosis
1. Drugs which increase calcium levels
A) Calcium salts
B) Vitamin D & analogues
2. Hormones
A) Sex hormones – estrogens and SERM
Androgenic progestins
Androgen
B) Other Hormones – Parathormone
Calcitonin

62. • 3. Other Agents
A) Bisphosphonates
B) Thiazide diuretics
C) Flouride
D) Stontium ranelate
E) Denosumab

63. Other drugs for osteoporosis
1. Strontium ranelate:
• It suppresses bone resorption as well as stimulates bone formation,
and has been introduced as a reserve drug for elderly women >75
years age who have already suffered osteoporotic fracture and are
unable to tolerate BPNs.
2. Denosumab: It is a human monoclonal antibody which inhibits
osteoclast differentiation and function as well as promotes their
apoptosis.
• It is a treatment option for postmenopausal osteoporosis when no
other drug is appropriate